The invention is generally in the field of methods and compositions for treating neurodegenerative diseases characterized by excess buildup of intracellular protein aggregates such as Parkinson's disease (PD), using viral and non-viral delivery systems that deliver therapeutic agents to specific regions of the brain. More specifically, using an adeno-associated viral vector to deliver a nucleotide sequence encoding an inhibitor of apoptosis protein (IAP) to specific regions of the brain associated with such neurodegenerative diseases.
Neurodegenerative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual. Neuronal cell death can occur as a result of a variety of conditions including traumatic injury, ischemia, degenerative disease (e.g., Parkinson's disease, ALS, or SMA), or as a normal part of tissue development and maintenance. In addition to Parkinson's disease, various other diseases, such as Huntington's disease, Alzheimer's disease and Multiple Sclerosis, ALS, fall within this category. These diseases are debilitating and the damage that they cause is often irreversible. Moreover, in the case of a number of these diseases, the outcome is invariably fatal.
Developmental cell death, or apoptosis has been implicated in neurodegenerative diseases. Apoptosis is a naturally occurring process thought to play a critical role in establishing appropriate neuronal connections in the developing central nervous system (CNS). Apoptosis is characterized morphologically by condensation of the chromatin followed by shrinkage of the cell body. Biochemically, the hallmark of apoptosis is the degradation of nuclear DNA into oligonucleosomal fragments. DNA laddering precedes cell death and may be a key event leading to death.
Progress is being made on many fronts to find agents that can arrest the progress of these diseases. Nonetheless, the present therapies for most, if not all, of these diseases provide very little relief. One problem has been the relevance of current animal models to human disease. To date, the cause of neuronal death has remained elusive. The gold-standard animal models for PD involve rapid destruction of dopamine neurons using chemicals which are fairly specific for dopamine neurons. These chemical toxins, which include 6-hydroxydopamine (6OHDA) and MPTP, cause oxidative damage to dopamine neurons in both rodents and primates. These models can be useful to test the efficacy of new therapies designed to improve the symptoms of PD, since such treatments are designed to intervene after cells have died or become dysfunctional, regardless of the cause of cell death. In order to test the value of protective or curative strategies, however, the mechanism of cell death must be relevant to human disease otherwise successful experimental studies will not translate into effective human therapy.
Accordingly, a need exists to develop therapies that can alter the course of neurodegenerative diseases. More generally, a need exists for better methods and compositions for the treatment of neurodegenerative diseases in order to improve the quality of the lives of those afflicted by such diseases.